Other Emerging Effects of CB1 Antagonists

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Many studies conducted with rimonabant showed its pleiotropic effects from obesity to drug dependence and memory impairment (Bifulco et al., 2007a). In this section, we aim to mention recent findings on antitumor properties of rimonabant (and other antagonists) as these studies suggest that targeting the EC system, via modulation of the CB1 receptor, could be a promising therapeutic strategy for cancer management.

The studies conducted from the late 1990s on the endocannabinoid system have provided strong evidence for a key role of the endocannabinoid in the control of cancer cell growth, invasion, and metastasis development in a way dependent on CB receptor activation (for a review, see Bifulco and Di Marzo, 2002; Bifulco et al., 2006, 2007b).

It has been demonstrated that rimonabant attenuates the antitumor effects of anandamide-related compounds or other cannabinoid agonists in thyroid, breast, and prostate cancers (Bifulco et al., 2001; Grimaldi et al., 2006; Portella et al., 2003; Sarfaraz et al., 2005), the effects being dependent on CB1 receptor activation. In other tumor types, like glioma, rimonabant failed to revert the antiproliferative action of cannabinoid agonists whereas the selective CB2 antagonist, SR144528 (Sanchez et al., 2001) or a combination of the CB1/ CB2 antagonists can partially prevent this effect (Jacobsson et al., 2001). However, a 48-h preincubation with these antagonists seems to enhance the AEA-mediated cell death of glioma cells, suggesting a more complex mechanism of action (Maccarrone et al., 2000).

Considering the antitumor properties of the cannabinoid receptor agonists, it could be expected that cannabinoid receptor antagonists, like rimonabant, if used alone, would enhance proliferation of normal and malignant cells leading to cancer. Some data excluded this possibility, rather reporting that not only agonists to cannabinoid receptors but also antagonists, used alone, are able to inhibit cancer growth (Bifulco et al., 2004) or induce apoptosis in cancer cells (Derocq et al., 1998; Powles et al., 2005). The first observation of a rimonabant potential antitumor action was provided by our group in rat thyroid cancer cells (KiMol) in vitro and in thyroid tumor xenografts induced by KiMol injection in athymic mice. In this model, rimonabant was able to prevent partially the antitumor effect of the inhibitors of endocannabinoid degradation, and the anandamide metabolically stable analogue (Met-F-AEA). However, rimonabant, when used alone, in the same model and at the dose previously shown to counteract the Met-F-AEA effect did not enhance tumor growth exerting per se a significant antitumor effect both in vitro and in vivo (Bifulco et al., 2004; Fig. 7.1). Interestingly, micromolar concentrations of rimonabant decreased viability of primary mantle lymphoma cells isolated from tumor biopsies of two patients (Flygare et al., 2005; Fig. 7.1). Moreover, rimona-bant showed an additive negative effect also on the viability of the mantle cell lymphoma cell line Rec-1 when combined with equipotent doses of AEA. Both Bifulco and Flygare supported the evidence of the antitumor action of rimonabant but they did not investigate or provide a molecular mechanism of action. They proposed that the observed effects could be ascribed to a tonic antiproliferative action mediated by the local endocan-nabinoids and the inverse agonist properties ofrimonabant on the receptor. These possibilities could explain the paradox whereby both CB1 agonists and antagonists display antitumor activity. Recently, we reported that rimonabant exerts antitumor effects on breast cancer in vitro and in a

Rimonabant

Thyroid tumour progression JJ in vivo & in vivo

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